Calcium plays an important role in many bodily functions, including nerve transmission, muscle contraction, pancreatic insulin release, intracellular signaling, hormone secretion, and hydrogen ion release from the stomach. Calcium is also a cofactor for some enzyme reactions and in blood coagulation. In addition, the body stores calcium in the bones and teeth and contributes to their structural integrity and function. Normal values of total calcium for humans range from about 8.8 to 10.3 mg/dL or 2.20 to 2.56 mmol/L. In adults, the total calcium content is 20 to 25 g/kg of fat-free tissue, and about 44% of this calcium is in skeletal tissue. Approximately 1% of skeletal calcium is freely exchangeable with that of the extracellular fluid. The reservoir of calcium in the bones maintains the concentration of calcium in the plasma constantly. About 40% of the calcium in the extracellular fluid is bound to plasma proteins such as albumin, about 5 to 15% is complexed with phosphate and citrate, and about 45 to 44% is in unbound, unionized form. Calcium is absorbed primarily in the duodenum as a result of the presence of active absorption sites in the upper GI tract.
Bones undergo continuous remodeling, with constant resorption and deposition of calcium into new bone. As humans age, the balance between bone resorption and deposition changes, and bone breakdown begins to exceed bone formation. The resulting bone loss can increase the risk of osteoporosis, especially in postmenopausal women. Adequate calcium intake, both through diet and with supplements, is important for both preventing and treating osteoporosis, osteomalacia, and other calcium-related conditions. In addition, some studies indicate that calcium intake may be associated with a reduced risk of colon cancer and a blood pressure-lowering effect.
Calcium supplements are widely administered to supplement dietary intake of calcium. However, the development of effective orally administrable calcium compositions has been hindered by a number of factors, including gastric emptying time, the variation in pH in different segments of the gastrointestinal tract, and the difficulty in localizing an oral delivery system in a selected region of the gastrointestinal tract. The bioavailability of calcium from different preparations sometimes varies, as often the manufacturing process has an effect on bioavailability. For most commercially available products, which are typically immediate-release formulations, bioavailability is generally low, and calcium absorption in adults is thought to average about 25-35% of the available calcium in the dosage form. Therefore, subjects taking calcium supplements often receive less than optimal amounts of calcium. With administration of currently available formulations, which are mostly immediate-release formulations, subjects often experience both hypercalcemia and hypocalcemia. Hypercalcemia refers to an excessive amount of calcium in the blood, and symptoms associated with hypercalcemia include nausea, vomiting, and calcium deposition in the heart and kidneys. Hypocalcemia refers to low levels of calcium in the blood, and symptoms associated with hypocalcemia include tingling, numbness, and muscle twitches. In severe cases, tetany, or muscle spasms, may occur. Subjects taking commercially available immediate release formulations, which typically contain high amounts of calcium, can experience hypercalcemia at first, then because the body is unable to absorb all of the elemental calcium at once, undissolved forms of calcium remain in the gastrointestinal (GI) tract. Between doses, subjects can sometimes experience hypocalcemia, as they are not receiving adequate amounts of calcium, and gastric side effects may be experienced due to the presence of undissolved calcium in the GI tract. There are difficulties in producing effective immediate-release formulations of calcium, as often a very large amount of elemental calcium must be present in the formulation. A currently marketed extended release formulation combines calcium carbonate and calcium citrate in one matrix/portion. It is designed to deliver calcium as a slow, sustained release profile with no immediate release component. This formulation also does not provide effective calcium supplementation, as initially, calcium is delivered very slowly (and in inadequate amounts, resulting in hypoglycemia) and there is inadequate absorption. In addition, undissolved calcium carbonate is present in the lower GI tract, and the high pH of the GI tract makes the calcium carbonate insoluble. The high incidence of gastric side effects creates a compliance issue for patients, and the severity of the side effects often results in patients skipping doses or discontinuing therapy all together.
There is a need in the art for orally administrable calcium compositions with good bioavailability which provide an effective amount of calcium to subjects with decreasing gastric side effects. The present invention addresses this need in the art by providing calcium compositions which provide improved bioavailability and absorption. The present invention also provides compositions which provide biphasic, controlled release of calcium. This type of release may enhance bioavailability and absorption by providing calcium in small continuous amounts, avoiding effects such as hypocalcemia. A first phase of release, such as immediate release of a calcium compound such as calcium carbonate, may be released immediately and absorbed mostly or fully in acidic media. A second phase of release, such an extended release of a calcium compound, such as calcium citrate, may be released. The benefits of the present invention include increased patient compliance, a higher amount of absorption of calcium with a lower dose required per dosage form, and reduced toxicity.